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Context: Primary ovarian insufficiency (POI) is defined by menopause before 40 years of age. POI prevalence is higher among women with autoimmune Addison's disease (AAD) than in the general population, but their clinical characteristics are insufficiently studied., Objective: To assess the prevalence of POI in a large cohort of women with AAD and describe clinical, immunological, and genetic characteristics., Methods: An observational population-based cohort study of the Norwegian National Addison Registry. The Norwegian Prescription Database was used to assess prescription of menopausal hormone replacement therapy (HRT). A total of 461 women with AAD were studied. The primary outcome measure was prevalence of POI. Secondary outcomes were clinical characteristics, autoantibodies, and genome-wide single nucleotide polymorphism variation., Results: The prevalence of POI was 10.2% (47/461) and one-third developed POI before 30 years of age. POI preceded or coincided with AAD diagnosis in more than half of the women. The prevalence of concomitant autoimmune diseases was 72%, and AAD women with POI had more autoantibodies than AAD women without (≥2 autoantibodies in 78% vs 25%). Autoantibodies against side-chain cleavage enzyme (SCC) had the highest accuracy with a negative predictive value for POI of 96%. HRT use was high compared to the age adjusted normal population (11.3 % vs 0.7%)., Conclusion: One in 10 women with AAD have POI. Autoantibodies against SCC are the most specific marker for autoimmune POI. We recommend testing women with AAD <40 years with menstrual disturbances or fertility concerns for autoantibodies against SCC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Premature ovarian insufficiency (POI), previously known as premature ovarian failure or premature menopause, is defined as loss of ovarian function before the age of 40 years. The risk of POI before the age of 40 is 1%. Clinical symptoms develop as a result of estrogen deficiency and may include amenorrhea, oligomenorrhea, vasomotor instability (hot flushes, night sweats), sleep disturbances, vulvovaginal atrophy, altered urinary frequency, dyspareunia, low libido, and lack of energy. Most causes of POI remain undefined, however, it is estimated that anywhere from 4-30% of cases are autoimmune in origin. As the ovaries are a common target for autoimmune attacks, an autoimmune etiology of POI should always be considered, especially in the presence of anti-oocyte antibodies (AOAs), autoimmune diseases, or lymphocytic oophoritis in biopsy. POI can occur in isolation, but is often associated with other autoimmune conditions. Concordant thyroid disorders such as hypothyroidism, Hashimoto thyroiditis, and Grave's disease are most commonly seen. Adrenal autoimmune disorders are the second most common disorders associated with POI. Among women with diabetes mellitus, POI develops in roughly 2.5%. Additionally, autoimmune-related POI can also present as part of autoimmune polyglandular syndrome (APS), a condition in which autoimmune activity causes specific endocrine organ damage. In its most common presentation (type-3), APS is associated with Hashomoto's type thyroid antibodies and has a prevalence of 10-40%. 21OH-Antibodies in Addison's disease (AD) can develop in association to APS-2.

Background: Women with systemic lupus erythematosus (SLE) are at risk of premature ovarian failure when treated with cyclophosphamide. This risk is increased when autoimmune thyroid disease is present. We undertook this study to determine whether the presence of ovarian autoimmunity also increased the risk of early ovarian failure among women receiving cyclophosphamide., Methods: We examined the records of women enrolled in the Lupus Family Registry and Repository, a cross-sectional study of ~3300 SLE subjects, for treatment with cyclophosphamide as well as menopausal status. We defined premature menopause as permanent, spontaneous cessation of menstruation before age 45. We measured anti-ovarian antibodies by enzyme-linked immunosorbent assay using stored sera., Results: There were 258 women treated with cyclophosphamide in whom presence of absence or premature menopause could by defined. A total of 169 (65.6%) had premature ovarian failure, while 89 (34.6%) did not. While anti-ovarian antibodies were present in a small percentage of patients, there was no association of premature menopause to either level of these antibodies (16.2 ± 20.3 units vs 17.4 ± 21.7 units, P = NS by Fisher's exact test), or positivity on this testing (11 of 169 [6.5%] positive vs 8 of 89 [8.9%], χ 2  = 0.53, P = .46, 95% CI 0.95-1.1). Neither renal disease nor hypothyroidism increased the risk of premature ovarian failure in these women receiving cyclophosphamide., Conclusion: Anti-ovarian antibodies among women with SLE are not associated with premature ovarian failure after treatment with cyclophosphamide., (© 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Problem: Premature ovarian insufficiency (POI) imposes great challenge on female reproduction. Whether immune disturbance in ovarian environment was implicated in POI remains unclear. We aimed to characterize the cytokine profile in follicular fluid (FF) and paired serum in patients with biochemical POI (bPOI)., Method of Study: Multiplex immunoassay containing 45 cytokines was performed for individual FF and paired serum samples from 35 bPOI patients and 37 matched controls. Cytokine profiles were compared between the two groups and cytokines correlated to ovarian reserve, and the rates of day-3 good-quality embryos were further analyzed., Results: In FF, significantly elevated level of chemokines MIP-1α (P = .043), CXCL8 (P = .024), IP-10 (P = .041), and eotaxin-1 (P = .015) as well as growth factors VEGF-D (P = .047), BDNF (P = .043), LIF (P = .002), and bFGF (P = .046) was found in bPOI patients compared to controls. Yet RANTES manifested an opposite trend with reduced levels among bPOI patients (P = .006). All these chemokines and growth factors in FF were significantly correlated with ovarian reserve (P < .05). In paired serum, cytokine signature was not likely accordant with that in FF between two groups, except for increased IP-10 (P = .032) in bPOI patients and its significant correlation to FSH and AFC (P < .05). Among all differentially expressed cytokines, RANTES in FF was correlated with the rate of day-3 good-quality embryos (P = .035)., Conclusion: Altered cytokine profile characterized by increased chemokines and growth factors was associated with early stage of POI, which may fuel the progression of the disease or even play a crucial role in the development of ovarian insufficiency., (© 2020 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

Studies demonstrated that deficiency in 17β-estradiol (E 2 ) in postmenopausal women influences their immune system. However, few studies have reported alterations in immunologic presentation during nonnatural menopause in young females. Here we compared the differences in immune response between young C57BL/6N mice with surgical or medical variectomy and aged C57BL/6N mice with the common feature of E 2 deficiency following Con A stimulation. We observed inverted CD4/CD8 ratios in the aged group and apparent reduced production of serum immunoglobin (Ig)G, IgA, and IgM in the surgical group, whereas changes in immune parameters in the medical group were moderate. These data suggested that the immunological response to Con A stimulus differed among the three groups and that E 2 deficiency was only partially responsible for the development of immune deficiency in aged mice.

Objective: Studies suggest that hormonal states affect disease characteristics in women with rheumatoid arthritis (RA). This study investigated how age at menopause affects disease in women presenting with early RA., Methods: This was a cross-sectional study of postmenopausal women with early RA under age 65 years at time of enrollment in the Canadian Early Arthritis Cohort. RA-related disease characteristics in women who had early age at menopause (EM; age at menopause <45 years) were compared to those who had usual age at menopause (age at menopause ≥45 years). The t-test was applied to continuous variables and the chi-square test to categorical variables. Multivariate logistic regression analysis was used to adjust for age at menopause, smoking, and use of exogenous hormones., Results: A total of 534 women were included; 93 were in the EM group. The age at RA onset was similar between groups. The EM group had higher mean patient global and pain scores and was more likely to be rheumatoid factor (RF) positive and meet the 1987 American College of Rheumatology criteria for RA. Using multivariate logistic regression, the EM group was more likely to be RF positive (odds ratio 2.2 [95% confidence interval 1.3-3.8], P = 0.005). Symptom duration, joint counts, Disease Activity Score in 28 joints, Health Assessment Questionnaire scores, and inflammatory markers did not differ between groups., Conclusion: These data suggest that early age at menopause, compared to usual age at menopause, is associated with seropositivity in women with early RA., (© 2015, American College of Rheumatology.)

Background & Aims: Chronic hepatitis C (CHC) and liver fibrosis progress more rapidly in men and menopausal women than in women of reproductive age. We investigated the associations among menopause, sustained virologic response (SVR), and liver damage in patients with CHC., Methods: We performed a prospective study of 1000 consecutive, treatment-naïve patients 18 years of age and older with compensated liver disease from CHC. Liver biopsy samples were analyzed (for fibrosis, inflammation, and steatosis) before patients received standard antiviral therapy. From women (n = 442), we collected data on the presence, type, and timing of menopause; associated hormone and metabolic features; serum levels of interleukin-6; and hepatic tumor necrosis factor (TNF)-α., Results: Postmenopausal women achieved SVRs less frequently than women of reproductive age (46.0% vs 67.5%; P < .0001) but as frequently as men (51.1%; P = .283). By multivariate regression analysis, independent significant predictors for women to not achieve an SVR were early menopause (odds ratio [OR], 8.055; 95% confidence interval [CI], 1.834-25.350), levels of γ-glutamyl transpeptidase (OR, 2.165; 95% CI, 1.364-3.436), infection with hepatitis C virus genotype 1 or 4 (OR, 3.861; 95% CI, 2.433-6.134), and cholesterol levels (OR, 0.985; 95% CI, 0.971-0.998). Early menopause was the only independent factor that predicted lack of an SVR among women with genotype 1 hepatitis C virus infection (OR, 3.933; 95% CI, 1.274-12.142). Baseline levels of liver inflammation, fibrosis, steatosis, serum interleukin-6 (P = .04), and hepatic TNF-α (P = .007) were significantly higher among postmenopausal women than women of reproductive age., Conclusions: Among women with CHC, early menopause was associated with a low likelihood of SVR, probably because of inflammatory factors that change at menopause., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Studies have demonstrated estrogen replacement therapy can improve the life quality of surgically menopausal women. However, the mechanisms in this process remain poorly defined. Here we show the effect of transdermal estrogen therapy on expressions of estrogen receptors and T-lymphocyte apoptosis in surgically postmenopausal women. Fifteen surgically menopausal women, 15 naturally menopausal women and 15 young women were chosen in our studies. Peripheral vein blood was collected and serum E2 and FSH levels were assessed using ACCESS. T-lymphocyte apoptosis and the expressions of Fas, FasL and ER subtypes and were determined. The serum E2 levels of surgically menopausal woman were significantly higher, and the "Improved Kupperman Index" and the scores of "Menopause Specific Quality of Life Questionnaire" in surgically menopausal women were significantly low after ERT. The rates of T-lymphocyte apoptosis and FasL expression in surgically menopausal women were decreased after ERT, but the difference was not significant. The expressions of ERalpha and ERbeta in two menopausal groups were significantly lower than those of the young group. They were both significantly up-regulated after 3 months of ERT. Transdermal ERT could significantly upregulate the serum E2 level, could improve menopausal symptoms and life quality of surgically menopausal women and upregulate ERalpha and ERbeta expressions on T lymphocytes, especially ERbeta. Thus, the low dose of transdermal ERT may have a protective effect on menopausal women's immune function and aging.

To investigate the effect of oral and transdermal estrogen replacement therapy (ERT) on the expression of different estrogen receptor (ER) subtypes and the secretion of immunoregulatory cytokines, we performed a clinical investigation on previously healthy women who had undergone a total hysterectomy and bilateral salpingo-oopherectomy. These women were randomly distributed into two groups: an oral ERT group and transdermal ERT group. Before and after ERT, the serum levels of estradiol (E2) and follicle stimulating hormone (FSH) were measured, ERalpha and ERbeta expression of peripheral blood T lymphocytes was tested, and secretion of specific immunoregulatory cytokines (IFNgamma, IL-2 and IL-4) by T lymphocytes was examined. Our results confirm that for both groups, the serum E2 level was increased after ERT (P<0.01) and the serum FSH level was decreased after ERT (P<0.01), with no significant difference in hormone levels between the two groups. ERalpha expression by T lymphocytes was significantly higher after ERT than before (P<0.01) in both groups. Levels of type 1 cytokines (IL-2 and IFNgamma), which were secreted by T helper 1 (Th1), after ERT were substantially decreased. The level of type 2 cytokine (IL-4), which were secreted by T helper 2 (Th2), was significantly increased after ERT (P<0.01 for the oral group and P<0.05 for the transdermal group). In summary, both oral and transdermal ERT increased serum E2 levels, decreased serum FSH levels and relieved the effects of peri-menopausal symptoms. These data suggest that both oral and transdermal ERT act to improve the balance of Th1/Th2 cytokines by the effects of estrogen potentially acting in T lymphocytes mainly through ERalpha.

Objective: To examine the predictors of time to premature gonadal failure (PGF) in patients with systemic lupus erythematosus from LUMINA, a multiethnic US cohort., Methods: PGF was defined according to the SLICC Damage Index (SDI). Factors associated with time to PGF occurrence were examined by univariable and multivariable Cox proportional hazards regression analyses: three models according to cyclophosphamide use, at T0 (model 1), over time (model 2) and the total number of intravenous pulses (model 3)., Results: Thirty-seven of 316 women (11.7%) developed PGF (19 Texan-Hispanics, 14 African-Americans, four Caucasians and no Puerto Rican-Hispanics). By multivariable analyses, older age at T0 (hazards ratio (HR) = 1.10-1.14; 95% CI 1.02-1.05 to 1.19-1.23) and disease activity (Systemic Lupus Activity Measure-Revised) in all models (HR = 1.22-1.24; 95% CI 1.10-1.12 to 1.35-1.37), Texan-Hispanic ethnicity in models 2 and 3 (HR = 4.06-5.07; 95% CI 1.03-1.25 to 15.94-20.47) and cyclophosphamide use in models 1 and 3 (1-6 pulses) (HR = 4.01-4.65; 95% CI 1.55-1.68 to 9.56-13.94) were predictors of a shorter time to PGF., Conclusions: Disease activity and Texan-Hispanic ethnicity emerged as predictors of a shorter time to PGF while the associations with cyclophosphamide use and older age were confirmed. Furthermore, cyclophosphamide induction therapy emerged as an important determinant of PGF.

Our study aimed at screening patients with primary Sjogren's syndrome (pSs) for the presence of antiovarian antibodies (AOAs). Detection of AOAs in patients' sera was achieved by ELISA, using bovine ovarian extract for coating. Western blot analysis and immunohistochemistry were used to characterize the antibody targets in the extract and to determine their locus on the bovine ovary, respectively. Specific AOAs were detected in 27% of 37 patients (two with premature menopause) and in none of the controls. Immunoreactivity mainly resided in five proteins of the extract with molecular masses 42, 49, 55, 64 and 72 kDa, and it might be attributed to their carbohydrate components. The antibody targets were mainly located in the granulosa and theca interna cells of the follicle, and in the endothelial cells and fibroblasts of corpus luteum. The detection, for the first time, of AOAs in a significant percentage of patients with pSs may suggest autoimmune oophoritis, clinical or subclinical.

The complex relationship between sex hormones and immune function suggests that sex hormone deficiency and estrogen replacement therapy (ERT) in post-menopausal women may have pleiotropic effects on immune function. For this reason, we aimed to investigate short-term effects of surgical menopause and ERT on immunity profile in peri-menopausal women. Seventeen healthy peri-menopausal women who were to undergo total abdominal hysterectomy and bilateral salpingo-oopherectomy (TAH + BSO) for uterine myoma were enrolled into this study. Three blood samples were collected from each patient: 1-day prior to surgery, 30 days after the operation (before ERT) and 30 days after transdermal ERT. The percentages of peripheral blood lymphocyte subpopulations, serum interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) concentrations were determined by flow-cytometry and ELISA, respectively. Following TAH + BSO, the percentage of CD8+ cells was increased ( P < 0.001 ) while the percentage of CD19+ cells, serum IL-4, and IFN-gamma concentration and the ratio of CD4+ to CD8+ cells were decreased ( P < 0.001, P < 0.001, P < 0.002, and P < 0.05 respectively). After ERT, this trend reversed and a decrease in the CD8+ cells ( P < 0.001 ), increase in the CD19+ cells percentages ( P < 0.02 ) and increase in serum IFN-gamma concentration ( P < 0.002 ) were observed. Although an increasing trend in the CD4+ to CD8+ ratio occurred by ERT, this was not significant. However, the decrease in the serum IL-4 concentration after TAH + BSO was not reversed by ERT. Hormone deficiency in post-menopausal women may cause an impaired immune response, and ERT can restore this phenomenon. Estrogen seems to have an important role in the regulation of immune function.

The incidence of premature ovarian failure is highly variable according to the familial context and the clinical symptomatology leading to diagnosis. Different etiologic mechanisms have been identified. Currently, the proportion of idiopathic premature ovarian failure tends to decrease owing to the better recognition of genetic and immunological anomalies. Initially this pathology was considered irreversible. However, for the past twenty years, stigmas of a resumption of ovarian function have been noted regularly. The optimisation of treatments therefore relays on a precise knowledge of pathophysiologic mechanisms underly the symptomatology.

The objective of this study was to: (1) assess the relative prevalence of ovarian, thyroid, nuclear, and cardiolipin antibodies associated with premature menopause and unexplained infertility and (2) compare ovarian and thyroid antibodies in premature menopause, unexplained infertility, and the general population. Autoantibodies were evaluated in women with premature menopause (n = 30), unexplained infertility with (n = 38) or without (n = 15) prior gonadotropin-induced ovulation, and normal cycling controls (n = 12) and in a population of women obtained from a blood bank (n = 53). Antibodies to ovary (OVAB), thyroid (THYAB; thyroid peroxidase and thyroglobulin), cardiolipin, and eight nuclear antigens were assessed by enzyme immunoassay. Organ-specific antibodies (ovary and thyroid) were present with significantly greater frequency than non-organ-specific antibodies (nuclear and cardiolipin) in premature menopause and unexplained infertility (60% (50/83) vs 16% (13/83) respectively; P < 0.0001). OVAB (53%, 44/83) were significantly more frequent than THYAB (30%, 25/83) in premature menopause and unexplained infertility (P = 0.0030). THYAB did not differ among all groups (P = 0.78). In premature menopause and treated or untreated unexplained infertility OVAB frequencies were 53, 61, and 33%, respectively, and were significantly more frequent than in the population (17%) (P = 0.0001). In unexplained infertility, individuals with no prior gonadotropin-induced ovulation had a lower frequency of OVAB than treated individuals (P = 0.07). The frequency distribution of optical density values for OVAB was significantly higher for premature menopause and unexplained infertility than for population or normal cycling women (P < 0.0001). Thus, only ovarian antibodies were significantly more frequent than other antibody markers of autoimmunity in premature menopause and unexplained infertility., (Copyright 1999 Academic Press.)

Used indirect immunofluorescence to put in evidence different types of auto-antibodies, involved in the etiopathogenesis of endocrine autoimmune diseases--thyroid auto-antibodies, anti-sperm antibodies, determined in the serum of both partners of the infertile couples, with infertility of unknown cause, ovary auto-antibodies, in early menopause cases. Besides the establish of a precise etiological diagnosis, this method offers the possibility to localize the auto-antibodies in the tissue and/or in the cells and also the chance to identify some types of auto-antibodies. In the case of thyroid auto-antibodies--antithyroglobulin and antimicrosomal antibodies, in the case of anti-sperm antibodies--anti-head, anti-intermediary piece, anti-acrosomal or anti-tail and anti-ovary antibodies--anti-oocyte, anti tecca granulosa or anti internal tecca.

By acting on the neuroendocrine system during the stress response, life events may greatly affect homeostasis and favor the appearance of disease. Here, we describe a relationship between stressful life events and premature ovarian failure. From a mechanistic point of view, we suggest an autoimmune origin for such premature ovarian failure on the basis of the role of cytokines in folliculogenesis and of their increased production during stressful life events.

Influence on the immune system activity by sex hormones has been widely reported. Fertile women are proner to the onset of autoimmune diseases than men, but this increased susceptibility disappears after menopause. The hormonal changes are very likely to be responsible for this event, but precise correlations between sex hormone levels and immune functions have not been defined. For this reason we have analyzed phenotype and natural cytotoxicity of peripheral blood lymphocytes (PBL) from 35 women in menopause, comparing them with the same parameters of 28 fertile and 8 postmenopausal women and correlating them with the hormonal pattern of each group. We have also considered 8 women with premature menopause. Hormonal levels have been detected by radioimmune assays, while PBL phenotype has been studied by immunofluorescence and FACS analysis. The natural killer (NK) cell activity has been calculated on the basis of a chromium release assay. Postmenopausal women showed a reduction of the number of total lymphocytes (1650 +/- 215 cells/mmc) in comparison to fertile women (2081 +/- 200 cells/mmc, P < 0.01). The decrease mainly involved B and CD4+ T lymphocyte subpopulations (P < 0.05 and P < 0.01, respectively). Women with premature menopause had lower percentage of CD4 lymphocytes (34% vs 47%, P < 0.01) and higher percentage of CD8 (30% vs 22%, P < 0.02) and NK cells (32% vs 14%, P < 0.009) than fertile women of the same age. The percentage of circulating lymphocytes expressing HLA class II antigens also resulted as being increased (22% vs 9%, P < 0.01). The number of total, CD2, CD4 T lymphocytes, B and NK cells correlated positively with LH and negatively with FSH serum levels (P < 0.05 and P < 0.002, respectively). PRL positively influenced CD2, CD4 and B lymphocyte numbers (P < 0.001). FSH and 17 beta-estradiol inversely affected CD8 and B lymphocyte numbers (P < 0.005 and P < 0.02, respectively). In conclusion, the increase of FSH and the decrease of PRL levels appear to be involved in the reduction of B and CD4 T lymphocytes thus lowering the risk for the onset of autoimmune diseases during and after menopause. Generalized activation of the immune system (raised expression of HLA class II antigens) with elevated numbers of cytotoxic subpopulations (CD8 and NK lymphocytes) is present in women affected by premature menopause suggesting the involvement of autoimmune dysregulation in the pathogenesis of this syndrome.

Seventy-five women with premature menopause presented to a reproductive endocrinologist over a 3-year interval. Thirty-five had an identifiable cause, usually a chromosomal defect, autoantibodies or cytotoxic chemotherapy. Forty had no apparent cause and of this group 5 conceived on hormone replacement therapy (HRT). Overall, this group of oestrogen deficient women had spent nearly half of their menopausal years to date, not on HRT.

The ovary was first documented as a target of autoimmunity over three decades ago yet today the aetiology and pathogenesis of autoimmune-mediated premature ovarian failure (POF) are poorly understood. Here, Roy and Helga Moncayo provide a brief overview of human autoimmune-mediated POF and the animal models of POF. They propose a model for the development of the disease, highlighting the role of supraphysiological levels of gonadotropins in inducing selectively antigenic mature ovarian elements.

The sera of 26 patients with premature ovarian failure were examined in order to detect immunoglobulin-G (IgGs) that can block FSH-induced in vitro granulosa cell DNA synthesis via, a Feulgen cytochemical bioassay system. The IgGs of four patients with polycystic ovary-like disease, five postmenopausal women, and four eumenorrheic women served as controls. Ovarian growth blocking IgGs were found in 21 of the 26 premature ovarian failure (POF) cases. The few cases characterized by the absence of follicles (streak ovaries) and the controls were negative. The ovarian blocking IgGs were far more prevalent in the POF cases than anti-cytoplasmic ovarian antibodies detected by an indirect immunofluorescence assay (only one of the 26 POF patients was positive). Our data hence confirm earlier expressed views that immune mechanisms are involved in a high proportion of patients with POF.

The presence of antiovarian antibodies in sera of women with premature ovarian failure was determined by an indirect fluorescent antibody assay using human ovarian tissue. Of 27 patients, 14 had positive ovarian fluorescence, compared with zero of 24 normal cycling controls (P less than .001) and one of 22 postmenopausal controls (P less than .01). In patients with autoimmune diseases, five of 17 demonstrated positive fluorescence compared with zero of 24 premenopausal controls (P less than .01). Immunoperoxidase staining revealed antigen concentrated at the granulosa cells and oocyte in nine of the 14 ovarian failure cases. The finding that a significant proportion of patients with premature ovarian failure have circulating antiovarian antibodies confirms previous studies, but localization of peroxidase staining to granulosa cells and/or oocytes represents a new finding in this study.

Tests for a range of autoantibodies, and counts of lymphocytes, B cells, T cells, and T cell subsets were performed in 45 Chinese patients with premature ovarian failure and 45 age-matched normal control subjects. Eight patients (18%) were positive for at least one autoantibody. Only one patient was positive for antiovarian antibody. Patients with autoantibodies had a significantly higher percentage of circulating B cells. The lymphocyte, T cell, CD4+, and CD8+ counts in patients with premature ovarian failure were significantly higher than those in the control group, but the CD4:CD8 ratio was significantly lower in women with premature ovarian failure. There was a significant negative correlation between plasma estradiol levels and CD8+ counts, and a significant positive correlation between plasma estradiol levels and CD4:CD8 ratios. The changes in lymphocytes and lymphocyte subpopulations in premature ovarian failure may be due to estrogen deficiency.

A 33-year-old female presented in 1966 with striking pigmentation, typical of Addison's disease, and amenorrhea. Endocrine assessment then showed normal basal serum cortisol and urinary hydroxysteroid levels, but serum cortisol did not respond to stimulation with either exogenous ACTH or lysine vasopressin. Steroid replacement treatment was started. Treatment was discontinued by the patient on her own initiative and after some yr she was lost to follow-up. Reassessment in 1986 showed a pigmented patient who had continued in good health. She had a normal basal serum cortisol level with circadian variation. Plasma ACTH levels were high but showed diurnal rhythmicity and suppressed incompletely with 2 mg or 8 mg of dexamethasone/24 h. Plasma aldosterone levels were normal and showed appropriate postural changes, but plasma renin levels were high. This patient has an immunological profile of autoimmune disease with positive adrenal, thyroid microsomal and gastric parietal cell antibodies with a history of a premature menopause which may also be of autoimmune origin. She has been seen over a 20-yr period and despite her appearance still has no biochemical evidence of glucocorticoid or mineralocorticoid deficiency. It is suggested that the patient had compensated hypoadrenalism, with serum cortisol levels maintained in the normal range by high plasma ACTH levels and serum aldosterone levels maintained by high renin levels. The long term result of the high ACTH levels was increased skin pigmentation.

The presence of other organ-specific autoimmune disorders in some patients with premature menopause has supported the concept of an autoimmune etiology. The authors analyzed the peripheral blood of 23 women with the diagnosis of premature menopause to detect the presence of monoclonal antibody-defined T-lymphocyte abnormalities and/or antiovarian antibodies. All subjects were less than 40 years of age with the duration of menopause ranging from less than 1 year to 11 years at the time of study. Thirty-five percent of the subjects had an elevated percentage of Ia+ (Dr-activated) T cells using monoclonal antibody L243. The percent T4 (helper) T8 (suppressor/cytotoxic) T cells and T4/T8 ratio were normal in the study group. Four subjects (approximately 17%) had elevated percentages of the age-related 3G5+ T cell subset. Two of the subjects with increased 3G5+ T cells also exhibited increased Ia+ T cells. Antiovarian steroid cell antibodies and antiadrenal cortical antibodies were present in approximately 9% of subjects. Anti-islet cell antibodies were not present. Thyroid antimicrosomal antibodies were present in 17% of subjects. Study subjects exhibited immunologic abnormalities that the authors hypothesize may play a role in the development of premature menopause in a larger percentage of patients than was previously suspected.

Eighteen patients with postmenopausal gonadotrophin levels and secondary amenorrhoea before the age of 35 years (premature ovarian failure, POF) were examined for the presence of cellular and humoral immune defects. Six patients had an abnormally low natural killer (NK) cell activity. The levels of circulating immune complexes were increased in six patients. Tissue antibodies were detected in six patients and two of these possessed ovarian antibodies. Leukocyte migration inhibition in the presence of ovarian antigen was slightly enhanced in three patients. Altogether 12 patients (66%) with POF had some immunological defect or defects suggesting that immune mechanisms are often involved in the aetiology of POF.

Premature ovarian failure is not uncommon. It can occur at any age and has important implications for both patient and clinician. Various therapeutic options are available, including in vitro fertilization with donor oocytes.